Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Fauber, Benjamin P.; Gobbi, Alberto; Savy, Pascal; Burton, Brenda; Deng, Yuzhong; Everett, Christine; La, Hank; Johnson, Adam R.; Lockey, Peter; Norman, Maxine; Wong, Harvey
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4109
• Page End: 4113
• Publication Date: 2015-10-01
• Subjects: RORc -- RORγ -- IL-17 -- Inflammation -- Autoimmune; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N -sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure–activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N -sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors.